In its broadest aspect, the present invention extends to a preparation for the controlled release of any chemical compound which has a particular activity, for example in the industrial or agricultural fields as well as in the medical and veterinary fields.
The present invention is described in detail herein with particular reference to the targeting of cytotoxic or cytostatic drugs, particularly the anticancer drugs doxorubicin (DOX) and cisplatin (CDDP), to a tumour site in a human or animal patient, however it will be understood that the present invention is not restricted to delivery of these particular anticancer drugs and in one preferred aspect extends to the delivery of any pharmaceutically active compound. As noted above, in its broadest aspect this invention extends to the controlled release of active compounds in general.
The incorporation of active cytotoxic drugs into controlled release matrices has been demonstrated to have potential useful applications for the treatment of cancer. These drug-polymer complexes can be administered by either direct injection into the tumour, or by embolisation in the form of microspheres into the arterial circulation of the target organ containing the tumour. Both embolisation into the arterial circulation and direct injection into solid tumour deposits are recognised forms of regional cancer therapy.sup.1.2. In the situation where the drug-polymer complex is embolised into the arterial circulation of a cancer bearing organ, the drug-polymer complex is manufactured in the form of small particles or microspheres, usually in the size range of 10-200 micron in diameter. When the drug-polymer complex is administered directly into the tumour, the same formulation may be used but without the necessity to form microspheres.
There are two basic requirements for this form of therapy to be effective. First, there is a need to localise sufficient quantities of the drug at the target site to have the desired cytotoxic effect. Second, there is a need to control the rate of delivery into the tumour milieu that will cause maximal cell destruction. To achieve these, it is essential to design or develop a polymer matrix system that can carry a high load of cytotoxic drug as well as provide a controlled or sustained drug release profile.
This often poses a problem for the formulation of sustained release matrices. It is frequently observed that matrices with a high drug loading release the drug rapidly, known as a "burst release" effect. This is most likely a result of weak bonding or superficial location of drug during the formulation of the high loading matrix. The conventional approach of using a coating technique may sustain the release of drug, but usually decreases the drug loading of the system.sup.3.
In the treatment of patients with cancer using regional chemotherapy, it is desirable for the drug-polymer complex to be degradable so that repeated doses can be given. Therefore, it is necessary to also construct a drug-polymer complex that will degrade within the tissues of the body.
For a sustained/controlled release system, the rate of drug release is determined to a large extent by the interaction between the drug and polymer matrices which is influenced by the method of drug incorporation. Drugs usually can be incorporated into the controlled release systems by the following simplified means: physical entrapment, ionic interaction and covalent binding. Physical entrapment allows medium to high drug loading but usually drug releases too rapidly. Ionic interaction can also give good drug loading but burst release can still be a problem. Covalent binding results in low drug loading and slow release rate. For biodegradable polymer matrices, the rate of degradation will also influence the drug release rate in vivo.
Doxorubicin (DOX), an anthracycline, is one of the most widely used drugs for the treatment of cancer. However, systemic administration of this agent can result in cardiotoxicity and other tissue damage and this has led to attempts to develop systems which target DOX more directly to the tumour site. One of the most promising of these is to inject microspheres containing DOX into the vasculature supplying the tumour with the intent that the microspheres become embolised and then release their drug, over a sustained period of time, into the environment of the tumour.
The original approach was to use microspheres prepared by polymerising albumin in the presence of DOX.sup.4-8 but these particles suffered from the disadvantages of having low loading capacities (1-13%) and an initial burst release profile. The inclusion of polyanionic compounds such as poly .alpha.-L-glutamic acid.sup.9, poly .beta.-L aspartic acid.sup.10 or heparin.sup.11 into the formulation of albumin microspheres has improved these loading and release characteristics to some extent. An alternative approach has been to use commercially available anion-exchange resins containing sulphonic acid groups to bind DOX.sup.12,13. These particles demonstrate high loading capacities and excellent release characteristics and have shown considerable promise in treating rat liver and rat hind limb tumours.sup.14,15. However, although non-toxic, these microspheres do not appear to degrade in vitro or in vivo which may limit their use in those patients where further applications of drug treatment are necessary.
One object of the work leading to the present invention has been to provide a system with high drug loading, sustained release but minimum burst release effect and biodegradability. In one aspect of this work, the present inventors have developed a biodegradable ionic polymer as the matrix, and used an ionic interaction as the drug-polymer binding mechanism which has achieved a high drug loading. The inventors have also developed the formation of drug-metal ions complexes to suppress the burst release. This has resulted in a carrier matrix with all the required properties for clinical use.